Cell Growth & Differentiation, Vol 7, Issue 1 83-90, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Topoisomerase II inhibitors affect entry into mitosis and chromosome condensation in BHK cells

H Anderson and M Roberge
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.

DNA topoisomerase II (topo II) is required at mitosis in yeast for high chromosome condensation and for chromosome segregation. Recent studies on intact mammalian cells using topo II inhibitors that do not stabilize cleavable complexes also suggest a requirement for topo II for complete chromosome condensation and perhaps also for entry into mitosis. We have investigated the effects of merbarone, ICRF-187, and aclarubicin, three topo II inhibitors that do not stabilize the cleavable complex, on entry into mitosis and on chromosome condensation in BHK and in tsBN2 cells. We have compared their effects with those of etoposide, a topo II inhibitor that stabilizes the cleavable complex. All inhibitors induced a concentration-dependent G2 delay or arrest that could be overcome with fostriecin or okadaic acid or by inactivation of RCC1 in tsBN2 cells. Mitotic chromosomes from cells treated with etoposide were extensively fragmented, whereas mitotic chromosomes from cells treated with merbarone, ICRF-187, or aclarubicin were intact but elongated and tangled. These results provide strong evidence that topo II activity is required in chromosome condensation for final coiling of the chromatids. Our results also indicate that protein phosphatases and RCC1 play a role in G2 delay induced by all inhibitors, whether they do or do not stabilize the cleavable complex.

This article has been cited by other articles:

				U. Schroeder, K. M. Bernt, B. Lange, J. Wenkel, J. Jikai, D. Shabat, R. Amir, N. Huebener, A. G. Niethammer, C. Hagemeier, et al. Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia Blood, July 1, 2003; 102(1): 246 - 253. [Abstract] [Full Text] [PDF]

				A. P. Null, J. Hudson, and G. J. Gorbsky Both {alpha} and {beta} Isoforms of Mammalian DNA Topoisomerase II Associate with Chromosomes in Mitosis Cell Growth Differ., July 1, 2002; 13(7): 325 - 333. [Abstract] [Full Text]

				T. Zima, V. Tesar, R. Sherwood, A. Sood, L.-C. Au, P. J. Richardson, and V. R. Preedy Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo Toxicol Pathol, October 1, 2001; 29(6): 591 - 599. [Abstract] [PDF]

				D. M. Sauve, H. J. Anderson, J. M. Ray, W. M. James, and M. Roberge Phosphorylation-induced Rearrangement of the Histone H3 NH2-terminal Domain during Mitotic Chromosome Condensation J. Cell Biol., April 19, 1999; 145(2): 225 - 235. [Abstract] [Full Text] [PDF]

				P. Grue, A. Grasser, M. Sehested, P. B. Jensen, A. Uhse, T. Straub, W. Ness, and F. Boege Essential Mitotic Functions of DNA Topoisomerase IIalpha Are Not Adopted by Topoisomerase IIbeta in Human H69 Cells J. Biol. Chem., December 11, 1998; 273(50): 33660 - 33666. [Abstract] [Full Text] [PDF]

				P. Muñoz, M. Z. Zdzienicka, J.-M. Blanchard, and J. Piette Hypersensitivity of Ku-Deficient Cells toward the DNA Topoisomerase II Inhibitor ICRF-193 Suggests a Novel Role for Ku Antigen during the G2 and M Phases of the Cell Cycle Mol. Cell. Biol., October 1, 1998; 18(10): 5797 - 5808. [Abstract] [Full Text]

				J. M. Fortune and N. Osheroff Merbarone Inhibits the Catalytic Activity of Human Topoisomerase IIalpha by Blocking DNA Cleavage J. Biol. Chem., July 10, 1998; 273(28): 17643 - 17650. [Abstract] [Full Text] [PDF]

				Y. Kwon, B. S. Shin, and I. K. Chung The p53 Tumor Suppressor Stimulates the Catalytic Activity of Human Topoisomerase IIalpha by Enhancing the Rate of ATP Hydrolysis J. Biol. Chem., June 9, 2000; 275(24): 18503 - 18510. [Abstract] [Full Text] [PDF]

				P. B. Deming, C. A. Cistulli, H. Zhao, P. R. Graves, H. Piwnica-Worms, R. S. Paules, C. S. Downes, and W. K. Kaufmann The human decatenation checkpoint PNAS, October 9, 2001; 98(21): 12044 - 12049. [Abstract] [Full Text] [PDF]